Hepatic but Not Extrahepatic Insulin Clearance Is Lowerin African American Than in European American WomenFrancesca Piccinini,1 David C. Polidori,2 Barbara A. Gower,3 and Richard N. Bergman1

Diabetes 2017;66:2564–2570 | https://doi.org/10.2337/db17-0413

African Americans (AAs) tend to have higher plasma insu-lin concentrations than European Americans (EAs); theincreased insulin concentrations have been attributed to in-creased secretion and/or decreased insulin clearance byliver or other tissues. This work characterizes the contribu-tions of hepatic versus extrahepatic insulin degradation re-lated to ethnic differences between AAs and EAs. By usinga recently developed mathematical model that uses insulinand C-peptide measurements from the insulin-modified,frequently sampled intravenous glucose tolerance test(FSIGT), we estimated hepatic versus extrahepatic insulinclearance in 29 EA and 18 AA healthy women. During thefirst 20min of the FSIGT, plasma insulin was approximatelytwice as high in AAs as in EAs. In contrast, insulin wassimilar in AAs and EAs after the 20–25 min intravenous in-sulin infusion. Hepatic insulin first-pass extraction was two-thirds lower in AAs versus EAs in the overnight-fasted state.In contrast, extrahepatic insulin clearance was not lower inAAs than in EAs. The difference in insulin degradation be-tween AAs and EAs can be attributed totally to liver clearance.Themechanismunderlying reduced insulin degradation in AAsremains to be clarified, as does the relative importance ofreduced liver clearance to increased risk for type 2 diabetes.

African Americans (AAs), particularly AA women, are atincreased risk for type 2 diabetes compared with their whitecounterparts (1,2). Diabetes incidence is estimated to be2.4-fold higher for AA women and 1.5-fold higher for AAmen than for white women and men, respectively (3). Themechanisms underlying increased risk in AAs are unex-plained. The elevated insulin in AA has been attributed toboth increased insulin secretion (4–6) and decreased clear-ance (7,8), with these changes already apparent in AA ado-lescents (5,6,9). Whether hyperinsulinemia in AAs reflects a

different metabolic pattern of insulin clearance relative towhites is of interest. Although substantial clearance of insulinoccurs in the liver, with a single-pass degradation that canbe .50% (10), insulin is also cleared by kidney and muscletissue. Is it possible that the relative importance of insulindegradation by liver, with regard to other extrahepatic tissues,differs among ethnic groups, and do these divergences con-tribute to differences in peripheral insulin concentrations?

Methods for estimating hepatic insulin degradation fromoral (10,11) and frequently sampled intravenous glucosetolerance (FSIGT) tests (12,13) have been developed on thebasis of deconvolution of plasma C-peptide concentrationsto calculate the insulin secretion rate (ISR) (14). A recentlydeveloped method (13) enables both hepatic and extrahe-patic insulin degradation to be estimated from FSIGT data.This new model exploits the fact that during the insulin-modified FSIGT, all the insulin appearing during the first20 min is from endogenous secretion (and hence is subjectedto first-pass hepatic extraction before entering the systemiccirculation), whereas the intravenous insulin infusion begin-ning at 20 min delivers insulin directly into the circulation.This approach was previously used to discriminate hepaticfrom extrahepatic clearance in a single population (13), butthe method has not been used to differentiate patterns ofinsulin degradation in various ethnic groups. We used thismethod to compare degradation of insulin in AA versusEuropean American (EA) participants.

RESEARCH DESIGN AND METHODS

Clinical StudyThe experimental protocol and enrollment criteria werepreviously described (15–17). Participants were 23 AAand 30 EA premenopausal women. Exclusion criteria weretype 1 or type 2 diabetes, polycystic ovary disease, disorders

1Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, LosAngeles, CA2Janssen Research & Development, San Diego, CA3University of Alabama at Birmingham, Birmingham, AL

Corresponding author: Richard N. Bergman, richard.bergman@cshs.org.

Received 5 April 2017 and accepted 7 July 2017.

This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db17-0413/-/DC1.

© 2017 by the American Diabetes Association. Readers may use this article aslong as the work is properly cited, the use is educational and not for profit, and thework is not altered. More information is available at http://www.diabetesjournals.org/content/license.

2564 Diabetes Volume 66, October 2017

METABOLISM

of glucose or lipid metabolism, use of medication that couldaffect body composition or glucose metabolism (including anti-hypertensive medication, oral contraceptives, and postmeno-pausal hormone replacement therapy), use of tobacco, alcoholconsumption.400 g/week, history of hypoglycemic episodes,and/or a medical history that contraindicated inclusion in thestudy. All participants had normal glucose tolerance. Partici-pants were informed of the experimental design, and writteninformed consent was obtained. The study was approved bythe institutional review board for human use at the Univer-sity of Alabama at Birmingham (Birmingham, AL).

ProtocolAll testing was done on an inpatient basis at the Universityof Alabama at Birmingham’s General Clinical Research Cen-ter (15–17). Participants were asked to consume at least250 g of carbohydrates for 3 days before admission andwere provided with a list of common foods and their carbo-hydrate content. They came to the General Clinical ResearchCenter the evening before testing. While there, participantswere given a standard meal consisting of 50% energy fromcarbohydrates, 30% from fat, and 20% from protein. Nofood was consumed for 12 h before the FSIGT, which wasperformed at 7:00 A.M. the following morning. After com-pletion of the glucose tolerance test, participants were givena late breakfast/lunch.

FSIGTInsulin sensitivity, insulin secretion, and insulin clearancewere determined from the FSIGT, as previously described(15–17). Blood was sampled three times over a 15-min pe-riod before glucose delivery. At t = 0, a bolus of glucose (50%dextrose, 300 mg/kg) was injected intravenously. Insulin(0.02 units/kg) was administered intravenously over a 5-minperiod from 20 to 25 min after the glucose injection. Post-injection blood was sampled (2.0 mL) at 0, 2, 3, 4, 5, 6, 8, 10,12, 15, 19, 20, 21, 22, 24, 26, 28, 30, 35, 40, 45, 50, 55, 60,70, 80, 100, 120, 140, 180, 210, and 240 min after glucoseadministration.

Laboratory AnalysesConcentrations of glucose, insulin, and C-peptide were an-alyzed in the Metabolism Core Laboratory of the GeneralClinical Research Center and Nutrition Obesity Research Center.Glucose was measured in 10 mL of sera with an Ektachem DTII System (Johnson & Johnson Clinical Diagnostics, Roches-ter, NY). This analysis had a mean intra-assay coefficient ofvariation (CV) of 0.61% and a mean interassay CV of 1.45%.Insulin assay sensitivity was 3.35 mIU/mL, mean intra-assay CV was 3.49%, and mean interassay CV was 5.57%.C-peptide assay sensitivity was 0.318 ng/mL, mean intra-assay CV was 3.57%, and mean interassay CV was 5.59%.

Mathematical Model for Hepatic and ExtrahepaticInsulin ClearanceHepatic and extrahepatic insulin clearance components werecalculated as described previously (13). The ISR was calculatedby a classic method: C-peptide deconvolution by using a

two-compartment representation and assumed kinetic pa-rameters (14). C-peptide and insulin secretion are assumedto be equimolar. Once calculated, the insulin infusion rate isused as input into the model. Hepatic delivery of insulin is givenas ISR + HPF $ P where P is the systemic plasma insulin con-centration and HPF is the hepatic plasma flow (specified as0.576 L/min/m2 [18]). Extrahepatic clearance is assumed tobe linear with parameter CLP. Hepatic clearance is assumedto be either linear (with parameter FEL describing hepaticfractional extraction) or saturable [with parameters Vmaxand Km and hepatic clearance = Vmax $ delivery/(delivery +Km)], and the best fit model is selected for each participant.For the saturable model, the hepatic fractional extrac-tion varies over time during the FSIGT; to provide a singlevalue for comparison with what is obtained from the linearmodel when depicting the distribution across participants,FEL is calculated in the prechallenge stage (corresponding toovernight-fasted values). The distribution volume for insu-lin (Vd) is also estimated; thus, a total of three (linear repres-entation) or four (saturable representation) parameters areestimated. Additional details and the full equations can befound in Polidori et al. (13).

Parameter Estimation and Statistical AnalysisThe model parameters were estimated by using least squaresand a simplex search algorithm (fminsearch in MATLAB,version 9). For each participant, the best-fit parameters forboth the linear and the saturable models were determined,and the preferred model was chosen by using the Akaikeinformation criterion (19). The difference between modeledand measured insulin concentration was quantified by usingthe normalized root mean square error (13). Data are pre-sented as mean (SD) unless otherwise stated. Between-group comparisons were done by using the Wilcoxon ranksum test; P , 0.05 was considered statistically significant.

RESULTS

Six of the 53 participants were not included in the analysisfor purely technical reasons. C-peptide measurements werenot available for three AA women, and three other women(one EA, two AAs) had plasma insulin concentration profilesindicating that the exogenous infusion was given consider-ably later than between 20 and 25 min, and the exact timingcould not be verified. Therefore, 47 participants were includedin the analysis.

Demographic information and basal plasma concentra-tions for the 47 participants are shown in Table 1. Insulinsensitivity and acute insulin response from the FSIGT alsoare summarized; additional information on these parameterscan be found in previous publications (15–17). The meanplasma glucose, insulin, and C-peptide concentrations aswell as the calculated ISR for both groups are shown in Fig.1. During the first 20 min (when all insulin comes fromendogenous secretion), mean plasma insulin concentrationswere approximately twice as high in AA as in EA womenas shown by area under the curve (AUC0–20 min = 215 [134]vs. 102 [72] pmol/L $ h, respectively; P = 0.0015). In contrast,

diabetes.diabetesjournals.org Piccinini and Associates 2565

after the intravenous insulin infusion at 20–25 min, result-ing plasma insulin values were similar between AA andEA participants (AUC20–60 min = 284 [130] vs. 235 [126]pmol/L $ h, respectively; P = 0.09).

Modeling of Plasma Insulin ProfilesFigure 2 shows the average measured and modeled insulinprofiles for EA and AA participants. Plasma insulin was welldescribed by the model in both groups, with mean (SD)normalized root square error = 8% (3%) in EAs and 9%(3%) in AAs. The saturable hepatic clearance model waspreferred in 33% (6 of 18) of the AA participants and 14%(4 of 29) of the EA participants; the linear hepatic clear-ance model was sufficient for the remaining participants.

The parameters were estimated with similar precision asin our previous study (13) (median CV values in this studywere 10% for Vd, 16% for CLp, 14% for FEL [linear model])and somewhat higher for the parameters of the saturablemodel (34% for Vmax and 60% for Km). Hepatic insulinextraction was dramatically lower in AA than in EAparticipants (Fig. 3A). Hepatic fractional extraction in theovernight-fasted state was only 17% (15%) in AAs comparedwith 44% (21%) in EAs (P , 0.001). In sharp contrast,extrahepatic clearance was not reduced in AA comparedwith EA participants (CLP = 15.9 [10.0] vs. 12.1 [8.7]mL/kg/min, respectively; P = 0.20) (Fig. 3B). Thus, 85%of insulin entering the liver escaped first-pass degrada-tion in AA participants, whereas only 55% of enteringinsulin escaped in EA participants. The relative contri-bution of hepatic insulin degradation to total insulinclearance was much lower in AAs than in EAs (Fig. 3Cand D), with 0–2-h mean values for the percentage ofwhole-body insulin clearance occurring in the liver of 23%(19%) in AA participants compared with 57% (28%) in EAparticipants (P , 0.001). Figure 4 shows hepatic first-passextraction (FEL) (Fig. 4A and B) and extrahepatic clearance(CLP) (Fig. 4C and D) distribution values in all AA and EAparticipants, respectively.

DISCUSSION

Previous studies (7) have demonstrated that genetic pre-disposition and environmental factors can contribute dif-ferently to the development of type 2 diabetes in differentpopulations (20,21). Specifically, AAs were discovered to

Figure 1—Average plasma glucose (A), insulin (B), and C-peptide (C) measurements and calculated ISR (D) for both EA and AA participants inthe first 60 min of the test.

Table 1—Demographic information for both EA and AAparticipants in the study

EA AA

n 29 18

Age (years) 26 (4) 25 (4)

Body weight (kg) 70 (13) 74 (16)

BMI (kg/m2) 25 (4) 27 (6)

Fasting plasma glucose (mg/dL) 91 (6) 90 (8)

Fasting plasma insulin (pmol/L) 62 (28) 71 (23)

Fasting plasma C-peptide (pmol/L) 552 (158) 515 (178)

AIRg (mU/mL $ min) 492 (386) 1,158 (755)

SI (1024 min21/mU/mL) 5 (3) 4 (4)

Data aremean (SD). AIRg, acute insulin response; SI, insulin sensitivity.

2566 Ethnic Differences in Insulin Clearance Diabetes Volume 66, October 2017

have a greater risk of type 2 diabetes than EAs likely be-cause of genetic inheritance and environmental aspects suchas westernization, sedentary lifestyle, and obesity (22).

The rate of degradation of insulin is a significant aspectin the development of type 2 diabetes. It has been demon-strated in Hispanic and AA cohorts that the lower metabolic

Figure 2—Measured and modeled plasma insulin profiles in EA (A) and AA (B) participants. Data are mean (SD) for measured and modeled (lineand shaded region) profiles.

Figure 3—Hepatic insulin fraction (FEL) (A) and extrahepatic clearance indices (CLp) (B) in EA vs. AA participants. Hepatic and extrahepaticcontribution to total insulin clearance in the first 120 min of the experiment in EAs (C) and AAs (D). Data are mean + SE. For participants wherethe saturable hepatic clearance model provided the best fit, FEL values shown in A were calculated in the prechallenge state.

diabetes.diabetesjournals.org Piccinini and Associates 2567

clearance rate of insulin is associated with a higher risk oftype 2 diabetes after adjusting for demographics, lifestylefactors, HDL cholesterol, indexes of obesity and adiposity,and insulin secretion (23). Reduced insulin clearance is im-portant because it is independently associated and inverselycorrelated with insulin resistance. In animal models withinduced obesity (24,25), reduced insulin clearance is accom-panied by increased insulin secretion in response to insulinresistance to maintain normoglycemia. In addition, insulinclearance is heritable in Mexican Americans, as confirmed byGuo et al. (26) who also identified regions on chromosomes15 and 20 that may influence it. To the best of our knowl-edge, similar genetic studies have not been done in AA pop-ulations. Thus, it would be interesting to determine whethergenetic factors are likewise relevant to insulin clearance in AAs.

In the current study population of EAs and AAs, the frac-tional liver insulin extraction is a striking two-thirds lowerin AAs than in EAs (15% vs. 44%) (Fig. 3A). This calculateddifference is consistent with the observed plasma insulinconcentrations (Fig. 1); AAs have a significantly higher in-sulin concentration immediately after glucose injection (i.e.,at the beginning of the test) when circulating insulin is onlydue to endogenous secretion (mean AUC0–20 min for plasmainsulin is 110% higher in AAs than in EAs), whereas thedifference between AAs and EAs is minimal after the insulininfusion, confirming previous reports (16,27). Insulin secre-tion after glucose administration is also higher in AAs thanin EAs (mean AUC0–20 min for ISR is 48% higher in AAsthan in EAs). Thus, both elevated insulin secretion and

decreased hepatic insulin extraction contribute to twofoldhigher levels of plasma insulin concentrations observed inAAs in the first 20 min compared with EAs.

The etiology of the lower hepatic but not extrahepaticinsulin degradation in AAs is not understood. Insulin deg-radation is a receptor-mediated system: the first step hap-pens when insulin is bound by its receptor, and then, thereceptor-bound insulin is internalized into the cellularendosomes with an energy-requiring absorptive endocytosis(28). After their formation, endosomes quickly acidify, andinsulin is dissociated from the receptor within the vesicle(28). As a result of the specific insulin-degrading enzyme,insulin degradation begins right before the acidification. Inaddition, enzyme CEACAM1 promotes insulin clearance byenhancing the rate of uptake of the insulin-receptor complex(29). Dissociated insulin is degraded in endosomes, trans-located to cytosol and degraded there, or delivered to othersubcellular compartments, such as peroxisomes (28). The re-ceptor is finally recycled in a vesicle back to the plasma mem-brane (28). Insulin-degrading enzyme and/or CEACAM1expression might be specifically reduced in AAs. Another pos-sible cause of the impairment of hepatic insulin clearance inAAs is reduced hepatic insulin receptor number or activity (30),making them less available for binding and endocytosis.Recently reviewed evidence that insulin action on glucoseoutput by the liver is mediated by indirect mechanisms (i.e.,suppression of adipocyte lipolysis) has indicated that insulinreceptor–mediated clearance may be differentiated frommetabolic actions of the hormone (31).

Figure 4—Distribution of hepatic insulin fractions (FEL) (A and B) and extrahepatic clearance individual indices (CLP) (C and D) in EA and AAparticipants (white and black bars, respectively) in ascending order with average values shown in gray areas.

2568 Ethnic Differences in Insulin Clearance Diabetes Volume 66, October 2017

The results of the current study confirm previous find-ings in adults and adolescents (32,33). AA adults and chil-dren have lower hepatic insulin clearance, greater acute insulinresponse, and decreased insulin sensitivity than their EAcounterparts. This might be a plausible effect of differencesin obesity-related phenotypes between AA and EA popula-tions, such as accumulation of fat depots and levels of IGF-I(34). This work strengthens prior observations that ethnic-ity and race profoundly affect glucose metabolism, suggest-ing that insulin clearance is a fundamental component.With regard to other ethnic groups, two studies comparinghepatic insulin extraction between AA and Hispanic girlsfound mixed results. In one study of overweight children,no between-group differences were seen (35), whereas in aprevious separate study from the same group in normalweight children, hepatic extraction was lower in AA childrenthan in Hispanic children (36).

The current study has some limitations. The number ofparticipants analyzed is not large, and the population ismade up of healthy women. Additional studies need to in-clude larger populations of both sexes with various levels ofglucose tolerance. Another limitation is that the ISRs in EAand AA participants were calculated by using the standardapproach in which individual participant C-peptide ki-netic parameters are calculated on the basis of demographicinformation and no ethnic differences in C-peptide kineticsare assumed. If C-peptide kinetics were considerably differentin AA women, some differences would be found in the cal-culated ISRs that would affect the estimated insulin clearanceparameters. Although more research into C-peptide kineticsin different groups would be of interest, such differences areunlikely to affect the major conclusions of this work because asensitivity analysis (data not shown) demonstrated that meanISRs in AA participants would need to be much higher(;45%) than estimated for the calculated hepatic extractionto be similar between EAs and AAs. This difference is welloutside the range of differences observed in any single partic-ipant between ISRs calculated from individually measuredC-peptide kinetic parameters and those of the adjusted groupparameters (14) and is therefore an unlikely explanation forwhy insulin clearance per se is lower in AAs. However, a com-parison of C-peptide parameters in AAs with those for whitesand/or American Indians would be of interest. Finally, futurestudies could measure liver fat content to determine whetherits increase contributes to reduced hepatic insulin clearance inAAs. In the current study population, hepatic lipids were notmeasured, but the cohort was made up of young, healthywomen unlikely to have elevated hepatic fat levels.

In conclusion, we have demonstrated that hepatic insulinclearance is 60% lower in AAs than in EAs. This striking dif-ference may contribute to the pathogenesis of type 2 diabetes,the prevalence of which is greater in AAs and in Africanpopulations (15). Reduced insulin clearance could cause pe-ripheral hyperinsulinemia, which could result in insulin re-sistance. The possibility that lower liver insulin clearancemay be an important pathogenic factor in AAs deservesconsideration.

No relevant difference in insulin clearance was found withregard to the extrahepatic component per se. Yet, the differ-ence in hepatic extraction alone could help to explain the hy-perinsulinemic response to glucose injection observed in AAs.The underlying biochemical mechanisms regulating the ethnicdifference in hepatic extraction are not totally clear, and assuch, more studies are needed of the mechanisms responsiblefor liver insulin degradation. Knowledge of these mechanismscould lead to appropriate treatment to improve clearance, ifit can be established that altered clearance contributes to thedevelopment of type 2 diabetes.

Funding. This study was supported by grants from the National Institute ofDiabetes and Digestive and Kidney Diseases (NIDDK) (R01-DK-58278, P30-DK-079626, P30-DK-56336, UL1-RR-02577). B.A.G. is supported by grants from NIDDK(R01-DK-096388, R01-DK-103863, P30-DK-079626, P30-DK-56336) and the Amer-ican Institute for Cancer Research. R.N.B. is supported by grants from NIDDK (DK-27619, DK-29867).Duality of Interest. D.C.P. is a full-time employee of Janssen Research &Development. R.N.B. is supported by grants from AstraZeneca and GI Dynamics andis an advisory board member of Ingredion. No other potential conflicts of interestrelevant to this article were reported.Authors Contributions. F.P. contributed to the data analysis and inter-pretation and wrote the manuscript. D.C.P. analyzed and interpreted data and edited themanuscript. B.A.G. designed the study, contributed to the data interpretation, and editedthe manuscript. R.N.B. originated the concept that reduced liver insulin clearance mightbe an important factor in pathogenesis of type 2 diabetes, contributed to the datainterpretation, and edited the manuscript. R.N.B. is the guarantor of this work and, assuch, had full access to all the data in the study and takes responsibility for the integrityof the data and the accuracy of the data analysis.Prior Presentation. Parts of this study were presented at the 76th ScientificSessions of the American Diabetes Association, New Orleans, LA, 10–14 June 2016.

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